Details

Autor(en) / Beteiligte

• Deng, Xin-Sheng
• Wang, Shuiliang
• Deng, Anlong
• Liu, Bolin
• Edgerton, Susan M.
• Lind, Stuart E.
• Wahdan-Alaswad, Reema
• Thor, Ann D.

Titel

Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers

Ist Teil von

• Cell cycle (Georgetown, Tex.), 2012-01, Vol.11 (2), p.367-376

Ort / Verlag

United States: Taylor & Francis

Erscheinungsjahr

2012

Quelle

Taylor & Francis

Beschreibungen/Notizen

• A distinct group of breast cancers, called "basal" or "triple-negative" (TN) cancers express both basal cytokeratins and the epidermal growth factor receptor, but fail to express estrogen receptors, progesterone receptors or HER2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemo-resistant, with p53 mutation, up-regulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin's effects were also studied in sublines with forced over-expression of constitutively active (CA) Stat3, as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin's efficacy in the clinical setting.